Increased Intra‐ and Extracellular Concentrations of γ‐Glutamylglutamate and Related Dipeptides in the Ischemic Rat Striatum: Involvement of γ‐Glutamyl Transpeptidase

Orwar, Owe; Li, Xiaoying; Andiné, Peter; Bergström, Carl-Magnus; Hagberg, Henrik; Folestad, Staffan; Sandberg, Mats

doi:10.1046/j.1471-4159.1994.63041371.x

Cited by 37 publications

(16 citation statements)

References 33 publications

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“…Glutathione efflux from brain cells is increased by potassium depolarization, iron (Fe 2+ ), inhibitors of mitochondrial respiration (malonate, 1-methyl-4-phenylpyridinium (MPP + ), 3-nitropropionic acid and cyanide), and after ischemia (32)(33)(34)(35)(36)(37)(38). In a previous study, we showed that the NMDA-mediated glutathione efflux was dependent on extracellular calcium but unrelated to dantrolene sensitive intracellular calcium release, osmotic change and glutathione-, or nitric oxide-synthesis (39).…”

Section: Introductionmentioning

confidence: 99%

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

et al. 2003

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N-Methyl-D-aspartate (NMDA)-receptor stimulation evoked a selective and partly delayed elevated efflux of glutathione, phosphoethanolamine, and taurine from organotypic rat hippocampus slice cultures. The protein kinase inhibitors H9 and staurosporine had no effect on the efflux. The phospholipase A 2 inhibitors quinacrine and 4-bromophenacyl bromide, as well as arachidonic acid, a product of phospholipase A 2 activity, did not affect the stimulated efflux. Polymyxin B, an antimicrobal agent that inhibits protein kinase C, and quinacrine in high concentration (500 μM), blocked efflux completely. The stimulated efflux after but not during NMDA incubation was attenuated by a calmodulin antagonist (W7) and an anion transport inhibitor (DNDS). Omission of calcium increased the spontaneous efflux with no or small additional effects by NMDA. In conclusion, NMDA receptor stimulation cause an increased selective efflux of glutathione, phosphoethanolamine and taurine in organotypic cultures of rat hippocampus. The efflux may partly be regulated by calmodulin and DNDS sensitive channels.

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Section: Introductionmentioning

confidence: 99%

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

et al. 2003

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“…Inhibition of GSH synthesis leads to increased free radical formation (Merad‐Boudia et al, 1998), increased nitric oxide synthase activity (Heales et al, 1996), decreased mitochondrial function (Heales et al, 1995 ; Merad‐Boudia et al., 1998), increased excitotoxic vulnerability (Bridges et al, 1991), and larger infarct areas after ischemia (Mizui et al, 1992). A decrease in tissue GSH concentration is observed after ischemia and excitotoxicity (Orwar et al, 1994 ; Shivakumar et al., 1995 ; Floreani et al, 1997) ; possible mechanisms include increased breakdown of GSH and inhibited synthesis or efflux of GSH and its oxidized form, GSSG. Indeed, efflux of glutathione occurs in rat brain in ischemia (andiné et al., 1991 ; Orwar et al, 1994 ; Yang et al, 1994), and a massive efflux of GSH from apoptotic nonneuronal cells is suggested as an early step toward cell death (van den Dobbelsteen et al, 1996 ; Macho et al, 1997 ; Ghibelli et al, 1998).…”

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confidence: 99%

“…A decrease in tissue GSH concentration is observed after ischemia and excitotoxicity (Orwar et al, 1994 ; Shivakumar et al., 1995 ; Floreani et al, 1997) ; possible mechanisms include increased breakdown of GSH and inhibited synthesis or efflux of GSH and its oxidized form, GSSG. Indeed, efflux of glutathione occurs in rat brain in ischemia (andiné et al., 1991 ; Orwar et al, 1994 ; Yang et al, 1994), and a massive efflux of GSH from apoptotic nonneuronal cells is suggested as an early step toward cell death (van den Dobbelsteen et al, 1996 ; Macho et al, 1997 ; Ghibelli et al, 1998).…”

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“…We have studied in earlier work the efflux of GSH and GSH metabolites following ischemia (Andiné et al., 1991 ; Orwar et al, 1994) and, with respect to GSH breakdown, we have been interested in the toxicity of cysteine (Abbas et al, 1997 ; Puka‐Sundvall et al, 1998). In this study, we explored the effect of the glutamate receptor agonists NMDA and kainate on net efflux, that is, increased extracellular concentration of GSH, GSSG, and amino acids.…”

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Glutathione Efflux Induced by NMDA and Kainate

Wallin¹,

Weber²,

Sandberg³

1999

Journal of Neurochemistry

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Neurotoxicity in acute as well as chronic neurological diseases may be partly mediated by oxidative stress caused by overactivation of glutamate receptors. A key component of the cellular defense against oxidative stress is reduced glutathione. In our earlier work, we have shown that ischemia in brain induces increased efflux, elevated metabolism, and decreased tissue concentrations of glutathione. In this study, we have evaluated the effect of glutamate receptor activation on the efflux of glutathione from hippocampus in vitro. NMDA and kainate induced a delayed increase in glutathione, taurine, and phosphoethanolamine efflux. Extracellular glutathione was recovered mainly in the reduced form (85-95%); the efflux was dependent on extracellular calcium but unrelated to dantrolene-sensitive intracellular calcium release and independent of glutathione or NO synthesis. The NMDA-induced efflux of glutathione was enhanced by blockage of ␥-glutamyl transpeptidase, indicating an increased transpeptidation of glutathione after NMDA receptor activation. Our results suggest that increased efflux of glutathione could be a factor in initiating nerve cell death via a change in intracellular redox potential and/or a decrease in the intracellular capacity for inactivation of reactive oxygen species.

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“…The extracellular levels of glutamate have been measured in various in vivo disease models by microdialysis and have been shown to reach concentrations of > 500 μM following spinal cord injury (McAdoo et al. 1999) and be maintained at concentrations of > 50 μM for 1–2 h during and following ischaemic insult (Orwar et al. 1994; Ritz et al.…”

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Glutamate induces release of glutathione from cultured rat astrocytes – a possible neuroprotective mechanism?

Frade

Pope

Schmidt

et al. 2008

Journal of Neurochemistry

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Glutamate is the major excitatory amino acid of the mammalian brain but can be toxic to neurones if its extracellular levels are not tightly controlled. Astrocytes have a key role in the protection of neurones from glutamate toxicity, through regulation of extracellular glutamate levels via glutamate transporters and metabolic and antioxidant support. In this study, we report that cultures of rat astrocytes incubated with high extracellular glutamate (5 mM) exhibit a twofold increase in the extracellular concentration of the tripeptide antioxidant glutathione (GSH) over 4 h. Incubation with glutamate did not result in an increased release of lactate dehydrogenase, indicating that the rise in GSH was not because of membrane damage and leakage of intracellular pools. Glutamate‐induced increase in extracellular GSH was also independent of de novo GSH synthesis, activation of NMDA and non‐NMDA glutamate receptors or inhibition of extracellular GSH breakdown. Dose–response curves indicate that GSH release from rat astrocytes is significantly stimulated even at 0.1 mM glutamate. The ability of astrocytes to increase GSH release in the presence of extracellular glutamate could be an important neuroprotective mechanism enabling neurones to maintain levels of the key antioxidant, GSH, under conditions of glutamate toxicity.

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Increased Intra‐ and Extracellular Concentrations of γ‐Glutamylglutamate and Related Dipeptides in the Ischemic Rat Striatum: Involvement of γ‐Glutamyl Transpeptidase

Cited by 37 publications

References 33 publications

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

Searching for Mechanisms of N-Methyl-d-Aspartate-Induced Glutathione Efflux in Organotypic Hippocampal Cultures

Glutathione Efflux Induced by NMDA and Kainate

Glutamate induces release of glutathione from cultured rat astrocytes – a possible neuroprotective mechanism?

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